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Keywords:

  • lithium;
  • stress;
  • hippocampus;
  • amygdala;
  • bipolar disorder;
  • glutamate;
  • plasticity

Objective

Lithium (Li) is often an effective treatment for mood disorders, especially bipolar disorder (BPD), and can mitigate the effects of stress on the brain by modulating several pathways to facilitate neural plasticity. This review seeks to summarize what is known about the molecular mechanisms underlying Li's actions in the brain in response to stress, particularly how Li is able to facilitate plasticity through regulation of the glutamate system and cytoskeletal components.

Method

The authors conducted an extensive search of the published literature using several search terms, including Li, plasticity, and stress. Relevant articles were retrieved, and their bibliographies consulted to expand the number of articles reviewed. The most relevant articles from both the clinical and preclinical literature were examined in detail.

Results

Chronic stress results in morphological and functional remodeling in specific brain regions where structural differences have been associated with mood disorders, such as BPD. Li has been shown to block stress-induced changes and facilitate neural plasticity. The onset of mood disorders may reflect an inability of the brain to properly respond after stress, where changes in certain regions may become ‘locked in’ when plasticity is lost. Li can enhance plasticity through several molecular mechanisms, which have been characterized in animal models. Further, the expanding number of clinical imaging studies has provided evidence that these mechanisms may be at work in the human brain.

Conclusion

This work supports the hypothesis that Li is able to improve clinical symptoms by facilitating neural plasticity and thereby helps to ‘unlock’ the brain from its maladaptive state in patients with mood disorders.